TY - GEN
T1 - Effects of BCG vaccination on the immune system and health of adults in Denmark
T2 - Exploring non-specific effects of BCG
AU - Madsen, Anne Marie Rosendahl
PY - 2024/9/13
Y1 - 2024/9/13
N2 - IntroductionThe Bacillus Calmette Guérin (BCG) vaccine is a live attenuated vaccine originally developed for tuberculosis prevention. It has been used for this purpose for the past 100 years. BCG has been shown to have non-specific effects on the immune system, and in some studies, to reduce the risk of unrelated infections. Observational studies and clinical trials in low-income settings have found BCG vaccination to be associated with reductions in overall child mortality which could not be explained by the prevention of tuberculosis alone. Furthermore, BCG may increase the serological response to subsequent vaccinations. These non-specific effects of BCG are possibly explained by induction of “trained immunity”: epigenetic and metabolic reprogramming of innate immune cells leading to increased antimicrobial activity.The aim of this PhD project was to explore the non-specific effects of BCG on the immune system and health of senior citizens in Denmark with the aim to reduce the risk of infection and improve the response to subsequent influenza vaccination. The COVID-19 pandemic broke out shortly after I began my research and resulted in both new opportunities and limitations for the project. Most importantly, it resulted in the inclusion of an extra clinical trial involving health care workers, which broadened my perspective on the effects of BCG to include younger adults as well as the elderly. MethodsThe thesis is based on three clinical trials: one involving health care workers (HCWs) and two involving senior citizens. All three were randomised, placebo-controlled, single-blinded, clinical trials.Study 1 aimed to test the effect of BCG vaccination on work absenteeism and risk of SARS-CoV-2 infection in Danish HCWs during the COVID-19 pandemic. We hypothesised that BCG might reduce susceptibility to and/or severity of COVID-19 based on the evidence of non-specific effects. BCG vaccination might thus offer some protection to frontline personnel in the wait for a specific COVID-vaccine. This trial included 1,221 HCWs from nine Danish hospitals recruited from May 2020 to January 2021. Participants were randomised 1:1 to a standard dose BCG or placebo and followed for six months with weekly questionnaires about symptoms and absenteeism. A blood sample was collected at inclusion and end of trial for measurement of SARS-CoV-2 antibodies. Study 2 aimed to explore the effect of BCG vaccination on the health of senior citizens with the objective to reduce their risk of acute infection, including the risk of COVID-19. This trial included 1,676 volunteers above 65 years of age recruited from September 2020 to December 2021 in Odense, Denmark. Participants were randomised 1:1 to a standard dose BCG or placebo and followed for 12 months with biweekly questionnaires concerning their health. After end of followup, clinical data was merged with data from the national health registers to gain information about use of antibiotics, hospitalisations, and deaths.In Study 3, we further explored the effect of BCG on the immune system of the senior citizens. We aimed to test the capacity of BCG to increase the antibody response to the inactivated influenza vaccine (IIV) and induce trained immunity in an elderly population. This trial included 273 participants over the age of 65 recruited in Odense, Denmark from October to November 2021. Participants were randomised 1:1:1:1 to four groups: three groups combining BCG and IIV in varying sequence and one control group (IIV only). Blood samples were collected before and after vaccination for assessment of change in influenza antibody titre. Participants were followed for six months post-randomisation for clinical infection (self-reported). From a subgroup of participants, we collected further blood samples for trained immunity analyses in which peripheral blood mononuclear cells (PBMCs) were isolated and cytokine production measured after homologous and heterologous stimulation in vitro.ResultsIn Study 1, BCG vaccination did not reduce absenteeism among HCWs, a proxy for the impact of the pandemic on the health care system. The relative risk of absenteeism comparing BCG with placebo was 1.23 with a 95% credibility interval of 0.98-1.53. There was a tendency of BCG being associated with more absenteeism and more self-reported infectious disease episodes after December 2020, corresponding to the time when influenza and COVID-19 vaccines were being administered to participants. BCG vaccination did not affect the risk of getting COVID-19, hazard ratio (HR) 1.31 (95% confidence interval 0.83-2.06) or being hospitalised, HR 0.84 (0.42-1.66). BCG revaccination of participants with a scar from previous BCG vaccination was associated with an increased risk of COVID-19 but also with a reduced risk of all-cause hospitalisation. We did not find any association between BCG vaccination and the serological response to COVID-19 vaccination. In Study 2, the incidence of acute infection tended to be lower in the BCG group compared with placebo, though the difference did not reach statistical significance in the main analysis, with a HR of 0.89 (0.78-1.02). However, BCG was associated with a significantly lower incidence of acute infection compared with placebo in participants from 65-74 years of age with a HR of 0.82 (0.70-0.96), and in participants, who had been COVID-19 vaccinated before enrolment, HR 0.65 (0.50-0.85). There was no effect of BCG on COVID-19 infections, HR 0.97 (0.75-1.26), or all-cause hospitalisation, HR 1.10 (0.80-1.50). BCG vaccination was, however, associated with more selfreported respiratory symptoms with a HR of 1.21 (1.10-1.33) compared with placebo.The mean fold change in influenza antibody titre four weeks after vaccination for all serotypes combined was 2.3-2.5. We found no significant difference between the treatment groups, the difference being -0.06 (-0.26-0.14) and 0.00 (-0.21-0.20) for groups 1 and 3 compared with group 2 (control group). There was no difference in the proportion of participant who seroconverted, defined as a four-fold rise in antibody titre, or the proportion who achieved seroprotection (antibody titre≥40). Group 4 was not included in the comparisons between groups as the paired samples were taken at different time points. The incidence of self-reported infection was similar between the groups, with a HR of 1.12 (0.73-1.70), 0.96 (0.63-1.49), and 1.06 (0.69-1.64) for groups 1, 3, and 4 respectively, compared with group 2. Administration of BCG together with IIV had modest impact on in vitro cytokine production compared with IIV alone.Discussion and conclusionBCG did not reduce the risk of COVID-19 or other infections in the HCWs. We found limited effect of BCG vaccination in seniors, both clinically and immunologically, and the serological response to IIV was not affected by BCG. BCG tended to be associated with more self-reported infectious symptoms though this did not lead to more severe outcomes. The results indicate that the effect of BCG may be modulated by previous BCG vaccination and interaction with other vaccines.Other trials examining the effectiveness of BCG in preventing infections in adults have been published. Generally, most trials including HCWs published in the aftermath of the pandemic have shown little or no effect of BCG in preventing COVID-19 or other respiratory infections. In contrast, several of studies like ours found a tendency for increased symptomatology in the BCG vaccinated subjects. This may be caused by immune activation by BCG or could, at least partly, be caused by differential reporting of symptoms due to incomplete blinding. Results from trials in elderly populations have been conflicting.Overall, the results seem compatible with the interpretation that BCG may have a protective effect against COVID-19 and infections in general in older or multimorbid populations, and in individuals who were primed with BCG in childhood. In contrast, there was no effect in healthier individuals. The results suggest that there is most to gain from BCG-induced immune training in people with weakened immune systems. Recent immunological data support this conclusion by pointing to baseline cytokine capacity being associated with the immune training effect of BCG on innate immune cells.In a combined analysis of mortality data from 11 trials of both HCWs and elderly, BCG versus placebo was associated with a 43% (11-64%) reduction in all-cause mortality over 6-12 months follow-up. This suggests that BCG, irrespective of its effect on COVID-19 and innate immune cells, may affect overall mortality.Future research should explore the effectiveness of BCG vaccination for prevention of infectious diseases in more frail populations. Studies should focus on severity of infection as well as overall morbidity and mortality to further enhance our knowledge of how we may best benefit from BCG’s non-specific effects.
AB - IntroductionThe Bacillus Calmette Guérin (BCG) vaccine is a live attenuated vaccine originally developed for tuberculosis prevention. It has been used for this purpose for the past 100 years. BCG has been shown to have non-specific effects on the immune system, and in some studies, to reduce the risk of unrelated infections. Observational studies and clinical trials in low-income settings have found BCG vaccination to be associated with reductions in overall child mortality which could not be explained by the prevention of tuberculosis alone. Furthermore, BCG may increase the serological response to subsequent vaccinations. These non-specific effects of BCG are possibly explained by induction of “trained immunity”: epigenetic and metabolic reprogramming of innate immune cells leading to increased antimicrobial activity.The aim of this PhD project was to explore the non-specific effects of BCG on the immune system and health of senior citizens in Denmark with the aim to reduce the risk of infection and improve the response to subsequent influenza vaccination. The COVID-19 pandemic broke out shortly after I began my research and resulted in both new opportunities and limitations for the project. Most importantly, it resulted in the inclusion of an extra clinical trial involving health care workers, which broadened my perspective on the effects of BCG to include younger adults as well as the elderly. MethodsThe thesis is based on three clinical trials: one involving health care workers (HCWs) and two involving senior citizens. All three were randomised, placebo-controlled, single-blinded, clinical trials.Study 1 aimed to test the effect of BCG vaccination on work absenteeism and risk of SARS-CoV-2 infection in Danish HCWs during the COVID-19 pandemic. We hypothesised that BCG might reduce susceptibility to and/or severity of COVID-19 based on the evidence of non-specific effects. BCG vaccination might thus offer some protection to frontline personnel in the wait for a specific COVID-vaccine. This trial included 1,221 HCWs from nine Danish hospitals recruited from May 2020 to January 2021. Participants were randomised 1:1 to a standard dose BCG or placebo and followed for six months with weekly questionnaires about symptoms and absenteeism. A blood sample was collected at inclusion and end of trial for measurement of SARS-CoV-2 antibodies. Study 2 aimed to explore the effect of BCG vaccination on the health of senior citizens with the objective to reduce their risk of acute infection, including the risk of COVID-19. This trial included 1,676 volunteers above 65 years of age recruited from September 2020 to December 2021 in Odense, Denmark. Participants were randomised 1:1 to a standard dose BCG or placebo and followed for 12 months with biweekly questionnaires concerning their health. After end of followup, clinical data was merged with data from the national health registers to gain information about use of antibiotics, hospitalisations, and deaths.In Study 3, we further explored the effect of BCG on the immune system of the senior citizens. We aimed to test the capacity of BCG to increase the antibody response to the inactivated influenza vaccine (IIV) and induce trained immunity in an elderly population. This trial included 273 participants over the age of 65 recruited in Odense, Denmark from October to November 2021. Participants were randomised 1:1:1:1 to four groups: three groups combining BCG and IIV in varying sequence and one control group (IIV only). Blood samples were collected before and after vaccination for assessment of change in influenza antibody titre. Participants were followed for six months post-randomisation for clinical infection (self-reported). From a subgroup of participants, we collected further blood samples for trained immunity analyses in which peripheral blood mononuclear cells (PBMCs) were isolated and cytokine production measured after homologous and heterologous stimulation in vitro.ResultsIn Study 1, BCG vaccination did not reduce absenteeism among HCWs, a proxy for the impact of the pandemic on the health care system. The relative risk of absenteeism comparing BCG with placebo was 1.23 with a 95% credibility interval of 0.98-1.53. There was a tendency of BCG being associated with more absenteeism and more self-reported infectious disease episodes after December 2020, corresponding to the time when influenza and COVID-19 vaccines were being administered to participants. BCG vaccination did not affect the risk of getting COVID-19, hazard ratio (HR) 1.31 (95% confidence interval 0.83-2.06) or being hospitalised, HR 0.84 (0.42-1.66). BCG revaccination of participants with a scar from previous BCG vaccination was associated with an increased risk of COVID-19 but also with a reduced risk of all-cause hospitalisation. We did not find any association between BCG vaccination and the serological response to COVID-19 vaccination. In Study 2, the incidence of acute infection tended to be lower in the BCG group compared with placebo, though the difference did not reach statistical significance in the main analysis, with a HR of 0.89 (0.78-1.02). However, BCG was associated with a significantly lower incidence of acute infection compared with placebo in participants from 65-74 years of age with a HR of 0.82 (0.70-0.96), and in participants, who had been COVID-19 vaccinated before enrolment, HR 0.65 (0.50-0.85). There was no effect of BCG on COVID-19 infections, HR 0.97 (0.75-1.26), or all-cause hospitalisation, HR 1.10 (0.80-1.50). BCG vaccination was, however, associated with more selfreported respiratory symptoms with a HR of 1.21 (1.10-1.33) compared with placebo.The mean fold change in influenza antibody titre four weeks after vaccination for all serotypes combined was 2.3-2.5. We found no significant difference between the treatment groups, the difference being -0.06 (-0.26-0.14) and 0.00 (-0.21-0.20) for groups 1 and 3 compared with group 2 (control group). There was no difference in the proportion of participant who seroconverted, defined as a four-fold rise in antibody titre, or the proportion who achieved seroprotection (antibody titre≥40). Group 4 was not included in the comparisons between groups as the paired samples were taken at different time points. The incidence of self-reported infection was similar between the groups, with a HR of 1.12 (0.73-1.70), 0.96 (0.63-1.49), and 1.06 (0.69-1.64) for groups 1, 3, and 4 respectively, compared with group 2. Administration of BCG together with IIV had modest impact on in vitro cytokine production compared with IIV alone.Discussion and conclusionBCG did not reduce the risk of COVID-19 or other infections in the HCWs. We found limited effect of BCG vaccination in seniors, both clinically and immunologically, and the serological response to IIV was not affected by BCG. BCG tended to be associated with more self-reported infectious symptoms though this did not lead to more severe outcomes. The results indicate that the effect of BCG may be modulated by previous BCG vaccination and interaction with other vaccines.Other trials examining the effectiveness of BCG in preventing infections in adults have been published. Generally, most trials including HCWs published in the aftermath of the pandemic have shown little or no effect of BCG in preventing COVID-19 or other respiratory infections. In contrast, several of studies like ours found a tendency for increased symptomatology in the BCG vaccinated subjects. This may be caused by immune activation by BCG or could, at least partly, be caused by differential reporting of symptoms due to incomplete blinding. Results from trials in elderly populations have been conflicting.Overall, the results seem compatible with the interpretation that BCG may have a protective effect against COVID-19 and infections in general in older or multimorbid populations, and in individuals who were primed with BCG in childhood. In contrast, there was no effect in healthier individuals. The results suggest that there is most to gain from BCG-induced immune training in people with weakened immune systems. Recent immunological data support this conclusion by pointing to baseline cytokine capacity being associated with the immune training effect of BCG on innate immune cells.In a combined analysis of mortality data from 11 trials of both HCWs and elderly, BCG versus placebo was associated with a 43% (11-64%) reduction in all-cause mortality over 6-12 months follow-up. This suggests that BCG, irrespective of its effect on COVID-19 and innate immune cells, may affect overall mortality.Future research should explore the effectiveness of BCG vaccination for prevention of infectious diseases in more frail populations. Studies should focus on severity of infection as well as overall morbidity and mortality to further enhance our knowledge of how we may best benefit from BCG’s non-specific effects.
U2 - 10.21996/kc2s-5t55
DO - 10.21996/kc2s-5t55
M3 - Ph.D. thesis
PB - Syddansk Universitet. Det Sundhedsvidenskabelige Fakultet
ER -